Sirtuins are a class of enzymes known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. Humans have seven sirtuins, Sirt1-7, that regulate a variety of biological processes, including aging, transcription, and metabolism. Therefore, small molecules that can regulate sirtuin activity can be used to treat a host of diseases.
The process by which sirtuins catalyze NAD-dependent protein lysine deacetylation can be summarized by the process shown in FIG. 1. Sirtuins have been conserved through evolution and have been implicated in a number of biological functions, perhaps foremost being the regulation of lifespan (e.g., Haigis, M. C., et al., Annu. Rev. Pathol. 5, 253-295, 2010; and Imai, S.-i., et al., Trends in Pharmacological Sciences 31, 212-220, 2010).
Sirt2, in particular, is one of the seven members of the Sir2-family of NAD+-dependent deacetylases (or sirtuins) in humans. Among the seven mammalian sirtuins, Sirt2 is the only one that is mainly localized in the cytosol (e.g., Michishita, E., et al., Mol. Biol. Cell 16, 4623-4635, 2005). Two cytosolic Sirt2 substrates have been identified and confirmed in cellular studies, α-tubulin and phosphoenolpyruvate carboxykinase (PEPCK) (e.g., North, B. J., et al., Mol. Cell 11, 437-444, 2003; Jiang, W., et al., Mol. Cell 43, 33-44, 2011). Sirt2 destabilizes microtubules by deacetylating α-tubulin Lys40. By deacetylating PEPCK and regulating PEPCK stability, Sirt2 also regulates gluconeogenesis.
The anti-cancer effects of small-molecule inhibitors of Sirt2 have been described, e.g., Heltweg, B., et al., Cancer Res. 66, 4368-4377, 2006; Zhang, Y., et al., Biochem. Biophys. Res. Commun. 386, 729-733, 2009. However, the known inhibitors generally have higher than optimal IC50 values against Sirt2, and also lack specificity against Sirt2. Moreover, attaining such specificity against Sirt2 could provide significant advantages for the treatment of particular types of cancer, such as breast cancer, and more particularly, triple negative breast cancer. Sirt2 has also been shown to be involved in neurodegenerative disease (e.g., Luthi-Carter, R., et al., Proc. Natl. Acad. Sci. USA, 107(17):7927-32, Apr. 27, 2010, and de Oliveira, R. M., et al., Front Pharmacol., 3:82, 2012). Thus, such inhibitors against Sirt2 could also provide an improved treatment of neurodegenerative disease.
Sirt5 is a mitochondrial sirtuin with weak deacetylase activity. However, it has since been discovered that it instead has very efficient desuccinylase and demalonylase activity (Du J. et al., Science, 334, 806-809, 2011). In particular, Sirt5 regulates the succinylation of many proteins and regulates their activity (Park, J. et al., Mol. Cell 50, 919-930, 2013), thereby possibly impacting the etiology and/or progression of a variety of diseases or conditions. One of the major phenotypes of Sirt5 deletion is the decreased ability to remove ammonia via synthesis and secretion of urea (Nakagawa, T. et al., Cell 137, 560-570, 2009; Yu, J. et al. Sci. Rep. 3, 2013).